Lactic acidosis

Bob Michell graduated from the University of London in Physiology and Veterinary Medicine in 1964. He is currently reader in the Department of Medicine, Royal Veterinary College, and chairman of the Board of Veterinary Studies at the University of London. He is author of 'Renal Disease in Dogs and Cats', co-author of 'Veterinary Fluid Therapy' and editor of 'An Introduction to Veterinary Anatomy and Physiology'. METABOLIC acidosis occurs in all species, and is associated especially with diarrhoea. In addition, in herbivores, particularly ruminants, lactic acidosis resulting from the rapid fermentation of carbohydrate is an important cause. This brief review emphasises the fluid and electrolyte disturbances associated with ruminant acidosis.


H2C03 ieCO2 H+ a HCO3 ie HCO3 (Equation A)
The simple equation above shows two essential features. * Even if CO2 or bicarbonate (HC03) are at abnormal concentrations in plasma, pH remains normal provided the C02:HCO3 ratio is normal. * Disturbances of H+ are reflected in elevated CO2 (respiratory acidosis) or depleted bicarbonate (metabolic acidosis). They may also arise from retention, ingestion or generation of an abnormal acid (H+) load, eg, from renal failure, grain engorgement, or during anaerobic metabolism (as in shock). These are all forms of metabolic acidosis, ie, plasma bicarbonate falls. Dilution of plasma bicarbonate by inappropriate fluid therapy is a further cause of metabolic acidosis. The most important cause of metabolic acidosis, certainly in young animals, is bicarbonate depletion through diarrhoea. Primary renal bicarbonate loss is seldom diagnosed in animals (though it does occur, eg, in dogs).

Diagnosis
Any acidosis is detectable through its effects on the buffer systems, notably bicarbonate. Equation A shows that because the bicarbonate buffer system involves three variables, the state of the system can be assessed from measurements of any two.

Blood gas electrodes
Blood gas electrodes measure pH (and thus indicate the severity of the acidosis) and PCO2 (thus showing whether it is respiratory or not) and most automatically calculate bicarbonate (showing whether it is metabolic or not).
They are essential for the recognition of respiratory acidosis (eg, during anaesthesia) and provide the most accurate acidbase diagnoses but are beyond the scope of most veterinary practice laboratories. Accurate diagnosis of respiratory acidosis/alkalosis also requires the use of anaerobically drawn arterial samples, which are seldom taken in veterinary practice.
'Total CO2' measurement Lactic acidosis If the concentrations in Equation A are expressed in mmol/1, HCO3:CO2 is normally 20:1. Thus if we take a blood sample and simultaneously liberate its CO2 and convert its bicarbonate to CO2 (by acidification) a measurement of all this CO2 (total CO2) is mainly a reflection of the original bicarbonate concentration. It is thus, despite being measured as CO2, an estimate of bicarbonate disturbances, ie, metabolic acidosis/alkalosis. Such measurements can be made inexpensively and swiftly, with good clinical precision, using venous whole blood in the Harleco Micro CO2 Apparatus (Groutides and Michell 1990).
All samples for acid-base diagnosis should be anaerobic (no bubbles, no dead space), drawn with free-flowing blood ideally from a reasonably calm, minimally restrained animal, without prior struggle or exertion.

Anion gap
In principle, the anion gap offers a simple estimate of the intensity of acidosis due to organic acids since their anions increase the normal gap between the measured major cations (Na and K) and anions (Cl and HCO3) (Michell and others 1989); anion gap is thus increased, for example, in ketoacidosis or lactic acidosis. For the present, however, it is beyond most practice laboratory facilities.

Clinical assessment
Clinical assessment of acidosis is essentially mythical, a pretence in the absence of a diagnostic measurement. Severe acidosis certainly causes clinical signs, eg, Kussmaul breathing (rapid and deep) and cardiovascular disturbances, but they are of little help in assessing severity except when extreme. The idea that in cases of diarrhoea severity of acidosis can be assessed from severity of dehydration may sometimes be true but can be dangerously misleading (Naylor 1986). In ruminal acidosis it is especially important to realise that the clinical signs may be obvious before the systemic acidosis reaches full severity (Mullen 1976).
It is, however, true that any diagnostic measurement must be viewed in its clinical context, not in isolation. In particular, acid-base measurements are affected by compensatory responses as well as primary disturbances.

Compensatory changes
Equation A enables us to understand that if the primary disturbance is metabolic acidosis (ie, depleted bicarbonate), then the compensatory change is a reduction in CO2 (hyperventilation) thus allowing the ratio, and hence plasma H+ concentration, to stay relatively normal.
Equally, if animals have a long standing respiratory alkalosis (reduced CO2) from chronic hyperventilation, the compensatory change to keep the ratio normal is a reduced bicarbonate concentration (increased urinary loss). This would resemble, purely on bicarbonate measurement, a metabolic acidosis but pH would tend to be increased, rather than decreased and, more important, clinical history and examination would not have suggested any cause of metabolic acidosis (indeed for this reason an acid-base measurement would probably not have been made).

Treatment
The general treatment of fluid, electrolyte and acid-base disturbances was the subject of a recent brief review (Michell 1989) and is discussed extensively in Michell and others (1989); it is not, therefore, considered further here.
Lactic acidosis occurs as a result of anaerobic metabolism (Type A) or a primary increase in the production of lactic acid (Type B) for other reasons, such as a result of the fermentation of excess readily soluble carbohydrate in herbivores (especially in ruminants) or as a complication of diabetic ketoacidosis in other species (May and Watlington 1990). Implicit in any lactic acidosis is not only that excess lactic acid is produced but at a rate beyond the capacity to metabolise it. Normally this is extremely high, provided the liver is healthy and well perfused; in severe dehydration or shock, however, restoration of circulating volume and thus of hepatic perfusion, is a key to resolving any associated lactic acidosis. This also explains why parenteral fluid therapy for dehydration with metabolic acidosis, or even shock, frequently involves the use of solutions containing lactate. It is a convenient bicarbonate precursor and the conversion occurs readily as circulation is restored.
Perhaps more fundamental than the presence or absence of hypoxia in lactic acidosis is the ability to generate normal supplies of ATP (Emmett and Seldin 1989).
The crucial link between the utilisation of glycogen or glucose and the generation of large quantities of ATP (using the Krebs cycle and oxygen) is pyruvate.
Pyruvate can be utilised (or generated) in three main ways.
* It can interconvert with alanine. * It can be used by mitochondria either (and most important) to 'fuel' the Krebs cycle, or to generate fatty acids or ketone bodies via acetyl coenzyme A. * It can generate lactic acid.
In the third instance, bicarbonate is used to buffer the acid load but subsequently, once pyruvate utilisation is restored to normal, the lactic acid is reconverted to pyruvate (especially in the liver) and the 'lost' bicarbonate is regenerated.
Hypoxia not only prevents pyruvate from being efficiently utilised by the Krebs cycle, it also speeds up glycolysis in order to compensate (very inadequately) for the reduced output of ATP; further pyruvate is thus formed, reinforcing the generation of lactic acid.
Lactic acidosis can arise in ruminants, as in other species, from shock, toxaemia and ischaemia. In fact very young calves with diarrhoea often have a degree of lactic acidosis as well as acidosis caused by bicarbonate loss (Naylor 1987). The classic cause of metabolic acidosis in adult ruminants, however, is sudden ingestion of excess grain. The fermentation associated with grain overload not only causes metabolic (lactic) acidosis but also dehydration by creating large numbers of osmotically active solute particles within the rumen and thus drawing fluid in from circulation and the tissues. The dehydration can be severe and any associated reduction of hepatic perfusion will impair the resolution of the lactic acidosis. Unlike most causes of lactic acidosis, the source of acid is truly exogenous rather than resulting from metabolic changes in the patient's tissues; indeed, the fermenting grain can be directly removed, together with much of the lactic acid still awaiting absorption.

Ruminant acidosis
So far, this could have been a general account of metabolic acidosis; why ruminant acidosis in particular?
Whereas the most common clinical cause of metabolic acidosis in general is bicarbonate loss due to diarrhoea, ruminants are particularly (but not uniquely) prone to two forms of acidosis resulting from excess ingestion of acid precursors (as in grain overload) or excess generation of acid (as in ketosis or, following ingestion in grain overload).
Both conditions involve the abnormal accumulation of organic acids: ketoacids in acetonaemia/ketosis, lactic acid in grain overload. Ketoacidosis results fundamentally from impaired glucose utilisation (and the associated catabolism, such as in starvation). It can be a serious complication of diabetes mellitus in dogs and cats but in ruminant acetonaemia it is seldom the primary therapeutic target which is instead to deal with the underlying disturbance of glucose metabolism. It is not, therefore, discussed further.

Excessive carbohydrate fermentation
The excess is commonly, but not exclusively, grain, especially when finely ground (because of greater exposure to ruminal flora).
It is the suddenness of the increased intake and the pre-existing carbohydrate intake which matter, rather than the absolute amount, essentially because they determine the likelihood that the ruminal flora can cope without undue adverse effect.
The key elements of the problem are: * Rapid proliferation (within six hours) of Gram-positive bacteria, notably streptococci, which generate lactic acid, lowering ruminal pH to below 5. This destroys much of the normal flora, especially protozoa, and directly damages the ruminal wall. * Generation of volatile fatty acids (VFA) initiates and reinforces the fall in ruminal pH and lactobacilli generate additional lactic acid, becoming increasingly important as pH decreases. * Though both D-and L-lactic acid are produced, it is the Disomer which accumulates as L-lactic acid is more readily metabolised (Kronfeld 1980) * Fermentation generates excess ruminal solute and the osmotic effects cause systemic dehydration and haemoconcentration (increased packed cell volume and total protein concentration) as noted above. Absorption of acid causes metabolic acidosis. Any associated diarrhoea increases both dehydration and acidosis. * Ruminal damage is increased by bacterial and fungal invasion and includes necrosis and gangrene when severe; hepatic damage may also follow. * Ruminal stasis develops, largely due to high concentrations of VFA, and impairment of colonic absorptive activity may cause diarrhoea. Ruminal distension by gas impedes venous return. * Apart from the effects of lactic acidosis there may also be those due to endotoxins (including endotoxic shock) and other toxins produced by the abnormal flora (Kopecha 1987). Acute or chronic laminitis may also follow; the importance of histamine in producing it has probably been overemphasised (Whitlock 1980). * Proliferation of thiaminase-producing bacteria may add to the potential complications of ruminal acidosis. * It is not just excess carbohydrate but the fact that it is too readily fermented which initiates the problem and this can result from a change in ruminal flora. Even on a constant concentrate intake, a fall in roughage can lead to lactic acidosis (Mullen 1976). In addition, sudden resumption of a previously reasonable intake, following a period of inappetence, can also cause the condition (Howard 1981). * Some authors (Whitlock 1980) emphasise that similar ruminal problems can occur much more mildly, ie, with abnormally low rumen pH and digestive disturbances but without the severe systemic consequences. In particular, they need not cause metabolic acidosis.
In horses the picture is basically similar but gastric distension is the paramount problem and much less lactic acid is absorbed, so the acidosis is less severe (and may even be replaced by metabolic alkalosis resulting from aspiration of gastric contents).
Gastric rupture and laminitis thus become the main concerns.

Prevention
Prevention is clearly a matter of husbandry (control of access) and nutrition (dietary composition, maintenance of roughage, avoidance of sudden-change). These should avoid the need for addition of buffers or antibiotics. Inoculation of ruminal fluid from cereal-adapted animals into unadapted cattle, thus adapting their ruminal flora, is feasible.

Treatment
The main therapeutic targets are to * Prevent further lactic acid production (includes prevention of further grain ingestion) * Correct the ruminal and systemic acidosis * Correct dehydration, hypovolaemia and shock * Restore normal gastrointestinal function Possible ancillary treatments include use of antihistamines, corticosteroids and thiamine; mild hypocalcaemia can occur and may justify use of-calcium borogluconate. Depending on how soon the problem is discovered, it will not immediately be clear how many animals in the group at risk will go on to develop symptoms, whether mild or severe.

Prevention of further acid production
The main approaches have been to remove the source by rumenotomy or ruminal lavage, or to inhibit the bacteria with antibiotics, which is more effective in preventing the onset of acidosis rather than restraining its intensity. Rumenotomy or lavage are probably needed for severe cases (pulse rate above 100, rumen pH below 5) and mild cases may benefit from lavage (Ig magnesium hydroxide/kg in 10 litres of warm water, preferably after repeated irrigation with 10 to 20 litres of warm water). Lavage has the additional benefit of diluting the osmotically active solutes drawing fluid from circulation.

Correction of acidosis
Apart from the use of intraruminal solutions (see above), parenteral fluids are usually needed. A standard recommendation (Blood and Radostits 1989) is to give 5 litres of 5 per cent sodium bicarbonate in 30 minutes (intravenously), followed by 150 ml/kg of 1-3 per cent bicarbonate over the next six to 12 hours.
Five litres of 5 per cent bicarbonate is 5 litres at 50 g/litre, ie, 250 g of bicarbonate; this is 250 x 1000 mg. Since the formula weight of sodium bicarbonate is 84 and a millimole is the formula weight in mg, the initial dose given to a 450 kg cow amounts to 84 x 450 mmol/kg = 6-6 mmol/kg The follow-up dose is 1 -3 x 1 -5 g/kg (since 100 ml contains 1-3 g): this is 1950 mg/kg which is 23 mmol/kg. It has to be said that the latter is an extremely high dose of bicarbonate in the absence of a diagnostic measurement to establish the severity of the metabolic acidosis, and particularly if additional alkali is placed directly into the rumen. Moreover as the animal recovers, reutilisation of lactate provides an additional source of bicarbonate. Excessive bicarbonate therapy therefore creates the risk of an 'overshoot' metabolic alkalosis.
When the bicarbonate deficit in plasma can be estimated, the usual approach to replacement is as follows.
In a severe acidosis the deficit in plasma bicarbonate could be (say) 20 mmol/litre. This deficit throughout extracellular fluid (20 per cent bodyweight) would total 20 x 450 in a 450 kg cow = 4 mmol/kg 5 Some argue that although bicarbonate is the primary extracellular buffer, acidosis involves intracellular buffers too, so that instead of just considering a fluid space of 20 per cent bodyweight, it could be anything up to 60 per cent. The dose would then be 12 mmol/kg. However, the safe approach to deficit therapy is to correct half the deficit initially (within six hours) and then the rest over the following six hours (onequarter) and on the next day (one-quarter) thus allowing reassessment of progress and, if necessary, of the dose required. Moreover, in calculating bicarbonate dosage, few would argue for the assumption of a fluid space greater than one-third of bodyweight.
In simple terms, the maximum bicarbonate dose obtained from these principles would be 6 mmol/kg initially, followed by 6 mmol/kg during the next 24 hours, subject to reassessment. If we assume a deficit of 15 mmol/litre in plasma, and an acidified fluid space of one-third bodyweight, the total deficit is 5 mmol/kg and the initial dose should be 2-5 mmol/kg, with a similar follow-up dose in the next 24 hours. Clearly the main factor influencing the effectiveness of the follow-up dose is the further generation/absorption of lactic acid. Evidence from other species certainly indicates a substantial risk from overuse of bicarbonate in the correction of metabolic acidosis, particularly lactic acidosis (Park and Arieff 1983). A safer solution may be 'carbicarb', a mixture of sodium carbonate and bicarbonate (Bersin and Arieff 1987). Clearly there is a need for research on the quantitative response to bicarbonate or to carbicarb in cattle with lactic acidosis. Obviously the use of lactate as a bicarbonate precursor is inappropriate in a severe primary lactic acidosis; this is therefore one of the instances where Hartmann's solution is not appropriate therapy for a metabolic acidosis.

Rehydration
The initial use of 5 litres in 30 minutes in a 450 kg animal, ie, 22 ml/kg/hour or 1 per cent bodyweight in the first halfhour, is certainly not excessive (and could desirably be increased by using more dilute bicarbonate, eg, the isotonic 1 * 3 per cent solution over an hour). The follow-up dose, 15 per cent of bodyweight, is reasonable for severe dehydration, however it should not all be provided as bicarbonate; isotonic saline or saline mixed with isotonic dextrose would be preferable, to avoid excess bicarbonate. It is important to restrict access to water in affected animals as they may be excessively thirsty. The main cause of their dehydration is essentially redistribution of body fluid into the rumen plus any loss due to diarrhoea. This involves electrolytes as well as water so that overdrinking can readily cause unwanted dilution of body fluids.

Restoration of normal gastrointestinal function
Apart from rumentomy or lavage (as noted above) and measures such as cud transfer (two to four litres of normal rumen liquor) to restore the normal flora (Mullen 1976), provision of good palatable hay and encouragement of movement in animals able to walk should assist early restoration of ruminal motility, as will the correction of any hypocalcaemia. The usefulness of parasympathomimetics is uncertain.

Summary
The first priority is to assess how many animals are at risk, to remove the source of excess carbohydrate, and to segregate animals requiring treatment from those requiring further observation.
Among animals needing treatment, those severely affected and requiring intensive therapy should be separated from milder cases. The former require rumenotomy or ruminal lavage followed by fluid therapy, the latter require parenteral fluids, with or without intraruminal fluid. The main objectives are to correct the systemic acidosis, to moderate the ruminal acidosis, to correct dehydration and prevent further generation of acid. Transfer of ruminal fluid from a healthy animal may help the restoration of the normal flora and the recovery of normal gastrointestinal function.
Despite the dehydration, unrestricted access to water is contraindicated. Supply of roughage is important in prevention and treatment as it promotes saliva flow and therefore the provision of natural ruminal buffers. Cud transfer can assist the re-establishment of the ruminal flora.
While the classic cause is sudden access to excessive quantities of grain, whether stored or in the field, changes in ruminal flora due to abrupt alterations of diet, or reductions in roughage intake, as well as a sudden increase in readily fermentable carbohydrate are all possible causes of lactic acidosis in ruminants.
Finally, despite the potential severity of the lactic acidosis, and the need to treat it, the risks of overuse of bicarbonate deserve emphasis. Diagnostic measurements to monitor the response to therapy are probably worthwhile.